AC waveforms biasing for bead manipulating chucks

ABSTRACT

AC waveforms biasing of bead transporter chucks and their accumulated charge sensing circuits tailored for low resistivity substrates and beads where if traditional DC quasi-static biasing potentials were used, the bead attraction potentials of the chuck would undergo rapid RC decay and cause the bead transporter chuck to stop working. Methods for selecting AC waveforms are given, including those that maximize the time average of the bead attraction potential at the bead collection zone of the bead contact surface.

The present invention is directed to devices for electrically picking upand dispensing grains in a spatially resolved manner. Specifically, thisdisclosure describes novel operation techniques and bead attractionelectrode biasing for bead transporter chucks. The invention providesfor the application of dynamic electric fields, such as those obtainedusing periodic pulses or other AC waveform components, to beadattraction electrodes in lieu of quasi-static electric fields that wereused previously to attract grains in bead manipulating chucks. Thesedynamic potentials can be used not only for attracting and retaininggrains, but in grain deposition sensing by measuring accumulated charge.

Electrostatic bead transporter chucks may be used to pick up,manipulate, transport, and then discharge or place grains or objects foruse in creating pharmaceutical, diagnostic or chemical compositions, orin performing assays or chemical analysis.

Bead transporter chucks act as clamps to hold or retain an object orobjects. Bead transporter chucks provide superior performance formanipulating grains, such as beads with diameters of 100-300 microns inchemical synthesis, such as combinatorial chemistry for solid phasesynthesis, or in an assay using PCR (polymerase chain reaction) or othermaterials such as powders, such as can be used to depositpharmaceuticals on a substrate.

For example, bead transporter chucks allow deposition of grains on anarray in a manner that is faster and more reliable than by the use ofmicropipettes, which can be inefficient, tedious, and time consuming.Another application for bead transporter chucks is synthesis ofpharmaceutical compositions, especially when used to combine compoundsto form compositions to be packaged into administration forms for humansor animals.

Grains containing one or more active ingredients may be deposited ontowell known carriers or substrates to make pharmaceutical dosage forms.Such grains may take the form, for example, of [1] a powder, such as drymicronized forms made by air jet milling processes; [2] microspheres;[3] extremely small structures, including fullerenes, chelates, ornanotubes; or [4] liposomes and fatty droplets formed from lipids orcell membranes.

The use of bead transporter chucks provides a customized and precisemethod for formulating drug compositions. The transporter can be usedwhen merging adjacent substrates carrying active ingredient to formmultidosage packs, in which dosage may decrease or increase from oneindividual unit to the next, as in hormone-based (e.g., birth control)drugs or antibiotic remedies. Using an electrostatic bead transporterchuck, dosages may be easily established or determined by the numberand/or type of grains dispensed onto each pharmaceutical carrier, or byusing electrical, optical, or mechanical dosage sensing. Using beadtransporter chucks to place active ingredients into pharmaceuticalcompositions can give high repeatability and is also advantageous whenthe active ingredients are not compatible, such as when the activeingredient is poorly soluble with carriers, or where a formulation orcarrier negatively affects the bioavailability or stability of theactive ingredient.

Although emphasis is placed in this disclosure on use of electrostaticbead transporter chucks that apply electric fields for grain retentionand/or release, the teachings given here can be applied to chucks thatalso use other phenomena, such as the use of compressed gas or vacuum,or electrically/chemically switchable adhesives, in controlling grainsand/or substrates. Electrostatic or quasi-electrostatic holdingmechanisms, however, are far more benign to delicate grain structuresthan traditional mechanical techniques, particularly when manipulatingbiologically active compounds where crushing, contamination, oroxidative damage must be minimized or eliminated.

The present invention can involve use of acoustic stimulation oracoustic dispensers, where acoustic energy, provided by a speaker orpiezoelectric device, is used to great advantage in grain control, thatis, propelling and/or tribocharging grains prior to, and especiallyduring, electrostatic manipulation. Tribocharging grains, as known inthe art, and described below, is more efficient and less damaging to thegrains than corona or plasma charging, which typically requires highapplied voltages of around 5 kV. Often, the sonically vibrating membraneor mesh used in such an acoustic grain dispenser can itself be used totribocharge the particles, eliminating the need to charge the grainsprior to their entry into the acoustic dispenser. The use of acousticdispensers allows polarity discrimination of grains, where wronglycharged grains are discouraged from being retained by the beadtransporter chuck. Other forms of charging and dispensing the grains canbe used, such as those described in U.S. application Ser. No.09/095,246, filed Jun. 10, 1998, pending. This concurrently filedapplication describes grain feed systems that use augers, jet mills orfluidized beds, gas-driven Venturi, and induction charging in grain feedtubing.

Many bead transporter chucks offer precision in being able to have one,and only one grain attracted, transported, and discharged for each beadtransporter chuck, or for each well, pixel, or individual spatialelement of the bead transporter chuck. In many cases, each pixel can beconsidered a tiny bead transporter chuck that is selectively andindependently controlled, such as planar chucks having individuallyaddressable x and y coordinates. This includes individually addressablepixels for different (multiple) grain types.

Grains manipulated by these bead transporter chucks (or beadmanipulating chucks) can be easily and controllably releasable, withwrongly charged grains (objects or grains having a charge of theopposite polarity desired) not occupying bead retaining or collectionzones on the bead transporter chuck. They function well for a wide rangeof grain diameters, including grains with general dimensions of 100microns and up, grains of much smaller dimensions, and also includingporous or hollow grains that have high charge/mass ratios. They alsooffer durability and re-usability, and good ease-of-use, includinghaving selectively or wholly transparent elements for easy movement andalignment of the chuck with intended targets or carriers.

Often, instead of depositing grains singly, bead transporter chucks areused to attract and place powder, such as powder containing activeingredient, on a substrate, such an edible substrate used forpharmaceutical dosage forms.

Electrodes used for attracting grains can be directly exposed, orcovered by a dielectric, to prevent ionic breakdown (sparking) in airand to make use of the properties of dielectric to enhance grain holdingcapacity. To control the amount of charged grains that may be attracted,an indirect method can be used where an attraction electrode is not useddirectly to attract grains--but rather is used to capacitively couple,as discussed below, to a pad or floating electrode. This floatingelectrode then develops image charges partly in response to the fieldgenerated by the bead electrode, and its operation is self limiting inthat it can only serve to attract a finite amount of charge before thepotential it generates is cancelled. This indirect charging method canbe more gentle, more precise, and less expensive to implement thancharging by corona discharge, particularly for high resolutionapplications. The instant invention can be applied to any number of beadtransporter chuck designs, but for illustration purposes, the chuckshown here attracts grains indirectly by way of one or more floatingelectrodes. Other useful electrode designs are illustrated in U.S.application Ser. No. 09/095,246, filed Jun. 10, 1998. Further techniquesemployed for precise dosage control include the use of sensingelectrodes used for grain deposition sensing. Sensing electrodes can bethought of as equivalent to bead transporter chucks dedicated to, andspecially monitored for accumulated grain charge.

However, bead transporter chuck designs and operation techniques thatuse simple static or quasi-static direct current (DC) potentials appliedto attraction electrodes to pick up and discharge grains can, undercertain conditions, encounter serious problems with grain attraction andcharge control.

One problem encountered is the conductivity of resistive substrates doesnot allow for charge retention needed for attracting grains or powder tothe substrates. Previous chucks were designed initially for use withquasi-static DC bias conditions, with selective application of DCpotentials to bead attraction electrodes for grain pickup. Generally,polarities were reversed to aid in grain discharge only. These chucksusing quasi-static grain attraction voltages were well suited for grains(e.g., powders) and substrates possessing high resistivity, such asinsulators or polymeric films having a bulk resistivity ρ on the orderof about 10¹⁵ Ω-cm.

Unfortunately, many bead transporter chucks using quasi-static DCpotentials applied to grain attracting electrodes are simply notresponsive or effective for lower resistivity grains or substrates.Because of the higher conductivity of low resistivity grains orsubstrates, DC or quasi-staticly generated charges within the grain orsubstrate decay rapidly using higher conductivity substrates or graincompositions. This rapid decay or leakage of charge comes about throughinternal movement of charges within the grain or substrate and by strayleakage, often aided by ambient humidity. This makes the beadtransporter chuck useless in attracting and retaining higherconductivity grains or powders. In using, for example, a beadtransporter chuck employing capacitive coupling to a floating electrode,there is only a finite amount of charge-inducing and attraction capacityavailable. With lower resistivity beads or substrates, theinduced-charge gathering potential on areas adjacent to the floatingpad, such as on a substrate, can decay to zero in a matter of a fewmilliseconds--and this is usually not enough time to accelerate,transport, and retain grains in intended bead collection zones.

Specifically, this invention addresses problems encountered withsubstrates having insufficient resistivity p, such as substrates havingbulk resistivities ρ of 10¹⁰ or 10¹¹ Ω-cm. As discussed below, thecircuit elements in many bead transporter chucks have electricalproperties that are characteristic of RC circuits (circuits havingsignificant resistance and capacitance elements), and the charge Q usedfor grain attraction that remains from an initial amount of attractioncharge Q₀ on a grain or substrate as a function of time can be describedby an exponential function

    Q=Q.sub.0 e(-kt)                                           (1)

having a characteristic time constant k equal to the overall resistanceR times the overall capacitance C:

    k=RC                                                       (2)

This time constant k is known as an "RC" time constant, and when R and Care expressed in SI units, it has units of seconds. The resistance R isderived from the resistivity by taking into account the cross-sectionalarea A and length I of the material in question:

    R=(ρl)/A                                               (3)

where ρ is the bulk resistivity or the equivalent, expressed in standardSI units of ohm-meters.

With prior bead transporter chucks and operation techniques, theresistivity ρ often has to be in excess of 1.1×10¹¹ Ω-cm in order tohave a time constant--that is, a time in which most grain attraction anddeposition must occur (see definition below)--on the order of seconds ormore. This problem is particularly acute when dealing with certainedible substrates, such as polyvinylacetate orhydroxypropylmethylcellulose which can have bulk or equivalent surfaceresistivities ρ well below 10¹¹ Ω-cm, where the resultant time constantis on the order of tens of milliseconds, which is usually not enoughtime to accelerate, transport, attract and retain beads.

The result of such low time constants is that because of the internalcharge movement and leakage, fewer grains than desired, or no grains,are attracted to intended bead collection zones and/or substrates duringbead transporter chuck operation. During synthesis or analysis, insteadof retaining a precise amount of ingredients carried by graiss into eachbead collection zone or substrate, little or no grain content isattracted and retained where desired, when using quasi-static attractingvoltages needed for efficient manipulation of the grains.

In seeking to avoid this lack of chuck response by greatly increasingthe applied (attraction) voltage, the attraction field can then be thentoo strong, causing grains to be attracted to unintended or wronglocations on the bead transporter chuck, or wrongly charged grains to beattracted to the bead transporter chuck or substrate. The same problemalso makes it difficult or impossible to perform accumulated chargesensing to gauge how much active ingredient has been attracted andretained by the bead transporter chuck.

It is important to note that many electrostatic bead transporter chucksmanipulate charged grains by making use of electrostatic image forces.As a charged grain approaches any metal or conductive surface, such as abead attraction electrode inside the grain dispenser or container, animage charge of opposite polarity will accumulate on that conductivesurface. This happens when mobile charge carriers in the conductivesurface are attracted by, or repelled by, the grain charge. Thismovement of charge in the conductive surface in response to a chargedgrain in the vicinity creates a potent image charge-induced holdingforce, or electrostatic image force. This electrostatic image forcetends to make the grain highly attracted to, and usually later, in tightcontact with, the conductive surface. It should be noted that dielectricgrains in stationary tight contact with a conductive surface have atendency to keep their charge for a period of days. With a grain veryclose to (e.g., contacting) any conductor, the electrostatic image forcegenerated tends to be greater than that due to any applied field used toaccelerate the grains toward the bead transporter chuck, and can be onthe order of hundreds of times the force due to gravity.

Typically grains to be transported or manipulated are tribo-chargedthrough frictional encounters and collisions, such as rubbing or bumpinginto surfaces, where charging can occur by charge induction or chargetransfer. The particular charge transfer mechanisms used in atribo-charging process will determine the applied voltages that shouldbe used on a tribo-charging mesh.

Also, grain motions and interactions, or collisions with obstacles--andeach other--inside a dispenser or container tend to randomize theirmotion, and this influences grain transport properties, as grains areaccelerated toward intended bead collection zones.

As discussed below, another problem present in quasi-static biasingtechniques involves grain deposition sensing, where an accumulatedcharge sensing method is used. The static nature of the appliedpotentials used to attract charged grains to the sensing electrodeintroduces opportunities for various types of noise--such as shot noise,Johnson (1/f) noise, thermal noise, Galvanic noise, and amplifiernoise--to destroy the accumulated charge sense information sought foreffective and precise grain accumulation or powder depositionmonitoring.

Methods for use of bead transporter chucks and acoustic grain dispensersare set forth in Pletcher et al., "Apparatus for electrostaticallydepositing a medicament powder upon predefined regions of a substrate,"U.S. Pat. No. 5,714,007, issued Feb. 3, 1998; Pletcher et al., "Methodand apparatus for electrostatically depositing a medicament powder uponpredefined regions of a substrate," U.S. application Ser. No.08/659,501, filed Jun. 6, 1996, now U.S. Pat. No. 6,007,630; Pletcher etal., "Method and apparatus for electrostatically depositing a medicamentpowder upon predefined regions of a substrate," copending U.S.application Ser. No. 08/733,525, filed Oct. 18, 1996; Pletcher et al.,"Apparatus for electrostatically depositing and retaining materials upona substrate," U.S. Pat. No. 5,669,973, issued Sep. 23, 1997; Datta etal., "Inhaler apparatus with modified surfaces for enhanced release ofdry powders," U.S. Pat. No. 5,871,010, issued Feb. 16, 1999; Sun et al.,"Acoustic dispenser," U.S. Pat. No. 5,753,302, issued May 19, 1998; Sunet al., "Electrostatic Chucks," U.S. Pat. No. 5,846,595, issued Dec. 8,1998; Sun et al., "Electrostatic Chucks," U.S. Pat. No. 5,858,099,issued Jan. 12, 1999; Sun, "Chucks and Methods or Positioning MultipleObjects on a Substrate," U.S. Pat. No. 5,788,814, issued Aug. 4, 1998;Loewy et al., "Deposited Reagents for Chemical Processes," U.S.application Ser. No. 08/956,348, filed Oct. 23, 1997, now U.S. Pat. No.6,004,752; Loewy et al., "Solid Support With Attached Molecules," U.S.application Ser. No. 08/956,737, filed Oct. 23, 1997, now U.S. Pat. No.6,045,753; Sun, "Bead Transporter Chucks Using Repulsive FieldGuidance," co-pending U.S. application Ser. No. 09/026,303, filed Feb.19, 1998; Sun, "Bead manipulating Chucks with Bead Size Selector,", U.S.application Ser. No. 09/047,631, now U.S. Pat. No. 5,988,432; Sun,"Focused Acoustic Bead Charger/Dispenser for Bead Manipulating Chucks,"U.S. application Ser. No. 09/083,487, filed May 22, 1998, pending.Additional instructional information is found in Poliniak et al., "DryPowder Deposition Apparatus," co-pending U.S. application Ser. No.09/095,246, filed Jun. 10, 1998, pending; Sun et al., "Apparatus forClamping a Planar Substrate," co-pending U.S. application Ser. No.09/095,321, filed Jun. 10, 1998, pending; and "Pharmaceutical Productand Method of Making," co-pending U.S. application Ser. No. 09/095,616,filed Jun. 10, 1998, pending.

It is therefore desirable to lower the resistivity or charge retentionrequirement for eligible substrates, allowing for acceleration andattraction of grains to intended bead collection zones or substratesusing grains or substrates that are otherwise not workable, as discussedabove. Preferably, this should be done while providing grain depositionin a preferred direction and location in conjunction with electrostaticimage forces.

Moreover, it is also desirable to have a means for dose monitoring, orgrain deposition monitoring. This should allow for accumulated chargesensing with precision in knowing how much charge accumulates onindividual substrates or at bead collection zones. Specifically, it isdesirable to be able to perform accumulated charge sensing while thebead transporter chuck is in operation, in an effective manner,overcoming the deleterious effects of various noise sources that plaguequasi-static biasing techniques.

In attracting and manipulating grains, image charges, electricpolarization, and grain mass and transport, play a role.

SUMMARY OF THE INVENTION

These problems are addressed by this invention by introducing ACwaveform biasing to attract grains on a bead contact surface of a beadtransporter chuck. The beads are directed to bead collection zones onthe bead contact surface using pulses or other dynamic, non-static beadelectrode bias waveforms which may included AC and DC components, and donot have to be periodic.

In one embodiment, a bead transporter chuck using AC waveform biasingfor attracting grains to a bead collection zone on a bead contactsurface, and for retaining and discharging grains from the beadcollection zone, comprises a bead electrode for selectively establishinga grain attracting field to the bead collection zone, with the beadelectrode shaped and configured in such a manner so that when an ACwaveform potential is applied to it, the grains are influenced by it andguided to selective retention by the bead electrode to the beadcollection zone.

The bead transporter chuck can optionally comprise a dielectricpositioned between the bead electrode and the bead contact surface. Itcan also optionally comprise a shield electrode positioned to shape theattractive field initiated by the bead electrode, and/or it can comprisea floating pad electrode, which in one embodiment is positioned betweenthe dielectric and the bead contact surface. The shield electrode can beshaped and configured so as to allow an electric field from the beadelectrode to emanate through the bead collection zone. The shieldelectrode can be, for example, positioned between the dielectric and thebead contact surface, and formed and configured as to surround, butremain electrically isolated from, the floating pad electrode. Ifdesired, a second dielectric may be positioned between the shieldelectrode and the bead contact surface or between the floating padelectrode and the bead contact surface, or both.

The bead transporter chuck can comprise a charge collector electrode ora coupling capacitor, or both, for monitoring accumulated charge on thebead collection zone of the bead contact surface.

The AC waveform potential used by the bead transporter chuck can be sochosen and configured so as to provide for a repeated attractionpotential at the bead collection zone of the bead contact surface, whenthe bead collection zone is proximate to a material, such as a lowresistivity substrate, that has an RC decay of a charge on the materialwhen the repeated attraction potential is applied. The AC waveformpotential is configured such that the time average of the grainattraction potential on the bead collection zone whenever the grainattraction potential acts is greater, on average, than that a secondgrain attraction potential that would be obtained when applying anequivalent time-averaged DC potential corresponding to the AC waveformpotential.

The AC waveform potential can also be chosen so as to maximize a grainattraction potential at the bead collection zone of the bead contactsurface, wherein an integral of the absolute value of V_(BCZ) withrespect to time, between a point A and a point B on the AC waveform,##EQU1## is maximized, with the value of the integral being greater thanobtained using a second AC waveform potential not so optimized.

The invention also provides for an accumulated charge sensing circuitfor a bead transporter chuck having a charge sensing electrode formonitoring accumulated charge on the bead collection zone of the beadcontact surface. This charge sensing circuit comprises a sensingcapacitor electrically connected between the charge collector electrodeand an AC bias source; and an electrometer electrically connectedbetween the AC bias source and the coupling capacitor so as to be ableto measure the potential of the sensing capacitor. The accumulatedcharge sensing circuit can be used in a process to determine when tostop grain accumulation or to monitor accumulation at various regions ona bead transporting chuck so that process adjustments, such as changesin grain-attracting potentials, can be made on-the-fly.

Another embodiment for an accumulated charge sensing circuit comprises atransformer having a primary winding and a secondary winding, theprimary and secondary windings each having first and second poles; thecharge collector electrode electrically connected to the first pole [BP]of the secondary winding of the transformer; a sensing capacitorconnected between a ground and the second pole [CP] of the secondarywinding of the transformer; an electrometer electrically connectedbetween the second pole [CP] of the secondary winding of the transformerand the ground; and an AC bias source connected across the first andsecond poles of the primary winding of the transformer.

Methods are disclosed for using a bead transporter chuck using an ACbias waveform, with steps including some or all of the following:

[a] applying a first potential to the bead electrode of the beadtransporter chuck to create a grain attracting field; and

[b] attracting and retaining a grain to the bead collection zone;

[c] reducing the first potential applied to the bead electrode, therebyreducing the grain attracting field sufficiently so as to discharge agrain from the bead collection zone to a desired location;

[d] aligning the bead transporter chuck with the desired location priorto step [c];

[e] using a bead transporter chuck that comprises a shield electrodepositioned between the bead electrode and the bead contact surface; theshield electrode shaped and configured to allow beads to be influencedby the bead electrode;

[f] grounding the shield electrode;

[g] applying a second potential of opposite polarity to the firstpotential of step [a] to the shield electrode during grain discharge.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a partial cross-sectional view of a bead transporter chuckthat can be controlled using the present invention, with structuresshown for one pixel or bead collection zone;

FIG. 2 shows the partial cross-sectional view of the bead transporterchuck of FIG. 1, with an attraction bias applied to the bead electrode,and with resultant symbolic electrical charges shown;

FIG. 3 shows the partial cross-sectional view of FIG. 2, with ahigh-resistivity substrate contacting or clamped to the bead transporterchuck so that it can receive grain deposition, and with resultantsymbolic electrical charges shown;

FIG. 4 shows the partial cross-sectional view of FIG. 3, with alow-resistivity substrate contacting or clamped to the bead transporterchuck so that it can receive grain deposition, and with resultantsymbolic electrical charges shown;

FIG. 5 shows an auxiliary planar view of the bead transporter chucksuggested by FIGS. 1-4, with the view taken in the plane of the floatingpad electrode and shield electrode;

FIG. 6 shows an equivalent circuit that can represent the electricalbehavior of the bead transporter chuck of FIGS. 3 and 4;

FIG. 7 shows three cartesian graphical waveforms representing appliedand resultant voltages in the bead transporter chuck as a function oftime, where a low-resistivity substrate is applied thereto, and usingquasi-static biasing;

FIG. 8 shows three cartesian graphical waveforms representing appliedand resultant voltages in the bead transporter chuck as a function oftime, where a low-resistivity substrate is applied thereto, and using ACwaveforms biasing;

FIG. 9 shows a cartesian graphical waveform representing a resultantvoltage at the bead collection zone in the bead transporter chuck as afunction of time, where a low-resistivity substrate is applied thereto,and using AC waveforms biasing;

FIG. 10 shows one possible equivalent circuit diagram that provides ACbiased charge and deposition sensing for at least one of the beadcollection zones of the bead transporter chuck shown in FIGS. 1-4;

FIG. 11 shows another possible equivalent circuit diagram that providesAC biased charge and deposition sensing for at least one of the beadcollection zones of the bead transporter chuck shown in FIGS. 1-4.

FIG. 12 illustrates how the bead electrode of a bead transporter chuckcan contact the substrate and even project out of a dielectric support,where in the illustration a shield electrode is positioned within thedielectric support.

DEFINITIONS

The following definitions shall be employed throughout:

"AC" (alternating current) shall denote any electric current thatreverses direction, perhaps periodically; or any applied potential ofchanging polarity. AC waveforms shall refer to any part or component ofsuch alternating currents, such as a rectified square waveformcomprising repeated single polarity pulses (see pulses below), with orwithout additional DC components.

"Acoustic" can refer to sound waves in air, but more generally mayinclude any alteration of properties of whatever elastic medium is usedinside the grain dispenser or grain manipulation theatre. Possibleelastic media include dry nitrogen or other gases; water; oil; propyleneglycol; refrigerants, such any of the compounds bearing the trademark,Freon® (aliphatic organic compounds containing the elements carbon anfluorene, and others halogens such as chlorine and hydrogen); sand; etc.Properties that may be altered include pressure, particle or moleculedisplacement, or density. Most commonly, this is achieved usinglongitudinal compressive waves in the elastic medium, provided by aspeaker (see definition below), but it can also occur by using jets orflow of the elastic medium.

"Bead contact surface" shall include all surfaces of the grainmanipulating chuck that are accessible to bombardment, contact orexposure to beads, regardless of whether such access is physicallyencouraged or discouraged. However, when discussing specifically thebead collection zone (see definition below), the bead collection zonecan then be considered separately from the remainder of the bead contactsurface, to facilitate description of its placement in the grainmanipulating chuck. The bead contact surface may be used to retain oraccommodate a substrate as discussed herein.

"Bead collection zones" shall include surfaces of the bead contactsurface at which grain attracting fields generated by bead electrodesattract and favor retention of a grain. The bead collection zones can befound at holes, apertures, or recessed areas of the bead contactsurface, or elsewhere.

"Bead electrode" shall connote any electrode meant to attract and retainmaterials things such as beads, objects, or particles. It can optionallycomprise a hole or aperture through which a grain or object can beviewed. In one embodiment, upon reducing of the electrical potentialapplied to it, a bead electrode can selectively allow discharge orrelease of any grain or beads retained.

"Conductor" and "electrode" shall include surfaces or sets of surfaces,continuous or non-continuous, that are capable of carrying electriccurrent. "DC" (direct current) shall denote any quasi-static electriccurrent that flows in one direction only, or any applied potential ofsingle unchanging polarity.

"Dielectric" shall refer to any dielectric material, such as electricinsulators in which an electric field can be sustained with a minimumpower input; the term is applied generally such that solid metals, ifmanipulated to meet this definition, for example with a radio frequencyapplied voltage, can be considered dielectrics. This dielectric materialneed not be solid (e.g., it can be hollow) and it can be made up ofsubstructures or different constituent dielectric subparts or materialtypes.

"Electrometer" shall connote any voltage measuring device.

"Electronic driver" refers to any power source that can be configured todeliver an appropriate AC waveform potential for operating the beadtransporter chucks pursuant to the description herein. The phrase"programmed to deliver the AC waveform potential" does not necessarilyimply computer control (though of course computer control is within theinvention), since other electrical components can be configured toestablish an AC waveform.

"Floating electrode" shall refer to any electrode electrically isolatedfrom ground or other electrodes and capacitively coupled to one or morebead electrodes for the purpose of attracting beads to one or more beadcollection zones.

"Grains" are, for the purposes of this application, either aggregates ofmolecules or particles, typically of at least about 3 nm averagediameter, preferably at least about 500 nm or 800 nm average diameter,and, in for example pharmaceutical manufacturing applications, arepreferably from about 100 nm to about 5 mm, for example, about 100 nm toabout 500 μm, and are preferably from about 100 nm to about 5 mm, forexample, about 100 nm to about 500 μm. Grains are, for example,particles of a powder. The term "grains" encompasses the term "beads,"which refers to any material thing such as a particle, object, tablet orreceptacle, capable of being manipulated. This shall include powder,spheres or beads made from polymer and reactive polymer masses, such asstyrene-based polymers used in the Merrifield type of solid-phasesynthesis. For respiratory administration of medicaments, for example, a1 to 10 micron range is useful for dry powders, with 4-8 micronspreferred.

"Pulse" shall refer to quick variation of applied potentials which areotherwise constant, or nearly constant. This variation shall be offinite duration in relation to the charge decay or charge leakage on asubstrate. In shape, a pulse or series of pulses may resemble spikes orparts or components of AC waveforms.

"Reducing," such as in the context of reducing applied potentials tobead electrodes to allow grain discharge, shall include reduction andreversal of polarity of the applied potential, such as going from +500 Vto -500 V or vice versa.

"Shield electrode" refers to electrodes that are used at or near thebead contact surface to shield (at least partially) a charged grain frombeing influenced by attraction fields emanating from a bead collectionzone, and/or to define and shape (narrow) the local electric attractionfield to encourage grain retention only in intended bead collectionzones.

"Speaker" can refer to any loudspeaker, transducer, machine, or device,such as a piezoelectric device, that is capable of providing acousticenergy, such as through pressure modulation; more generally, it is anydevice capable of altering the properties of the elastic medium usedinside the grain dispenser or grain manipulation theatre.

"Substrate" shall refer to any material body that receives oraccommodates beads in the course of using a bead transporter chuck. Itcan comprise, for example, a pharmaceutical dosage form into whichactive ingredients, in the form of grains, can be attracted andretained. The substrate can be a variety of materials such as an "ediblesubstrate," which is a material which is safe for an animal to consume,for instance because it is metabolized or because it passes through theanimal's system without causing any serious problems, or can besomething not often considered edible, such as stainless steel.Substrates can be, for example, clamped or placed onto the bead contactsurface of a bead transporter chuck, to receive grains in the form ofpowder, adjacent or over each bead collection zone.

"Time constant" shall refer to the time required for a physical quantity(such as the amount of electrical charge on a substrate) to either riseto (1-1/e) or approximately 63% of its final steady state value, or fallto (1/e) or approximately 37% of its final steady state value, when thephysical quantity varies as with time t as e^(kt).

Regarding electrode orientations, the invention is sometimes definedusing the terms "around," and "surrounding," such as where a shieldelectrode 10 surrounds a floating pad electrode F. When electrodes,conductors, or dielectrics are found on different levels or layers ofthe bead transporter chuck, "around" and "surround" are to beinterpreted in view of the areas of the bead contact surface to whichthe electrode or structure in question will map to by projecting eachpoint to the nearest point on the bead contact surface.

It is also important to note that although the terms electrostatic andquasi-electrostatic are used throughout this disclosure, no limitationis meant or intended in terms of time variations of charge on electrodesand conductors used in the present invention. Electrical currents canand will flow in the course of using the bead manipulating chucks asdescribed, in order to apply and remove electric charge as required,particularly as AC waveforms, pulses, or other dynamic appliedpotentials are used when using the instant teaching. Although the term,electrical, may also be used in lieu of the term, "electrostatic," adistinction of convenience is made, so as to make clear that whileelectrical or electrostatic forces are used to attract beads, and thefrequency of the applied potentials used is relatively low, that is, notmeant to be on the order of radio or microwave frequencies, as discussedbelow. Potentials refer to electric potentials or applied voltages.

DETAILED DESCRIPTION OF THE INVENTION

Referring to FIG. 1, a partial cross-sectional view of a beadtransporter chuck that can be controlled using the present invention isshown, with structures given for one pixel or bead collection zone. Thebead transporter chuck shown is merely illustrative, being given byexample only to facilitate description. It is one of many typical beadtransporter chucks and alternate chuck configurations that can be usedto implement this invention.

At the top of this figure, the bead transporter chuck comprises a planarbead electrode 9 that is used to provide a grain attracting field.Affixed to a bottom face of bead electrode 9 is a planar firstdielectric layer D1. First dielectric layer D1 is applied to, or has itsface affixed to the bead electrode 9 in a parallel plane using anynumber of techniques known in the art, such as laminating; powderdeposition; or thin film deposition, such as magnetron sputtering, orelectron beam evaporation. Dielectrics that may be used include commonlyavailable materials such as Corning Pyrex 7740 glass (Corning Inc,Corning, N.Y.); or polyimide resin; a typical thickness is 10-20 mils.Affixed to the other face of first dielectric layer D1 in a similarmanner is planar shield electrode 10, which comprises an aperture toaccommodate a floating pad electrode F, with the floating pad electrodeF coplanar with, and surrounded by shield electrode 10.

Referring now also to FIG. 5, an auxiliary planar view of the beadtransporter chuck is shown, with the view taken in the plane of thefloating pad electrode and shield electrode. Floating pad electrode Fcan have a circular shape, as shown, and is also affixed to the otherface of first dielectric layer D1. Floating pad electrode F iselectrically isolated from the shield electrode 10. This can beaccomplished using an air gap, as shown; alternatively, an insulator maybe used at the gap to further electrically isolate shield electrode 10from floating pad electrode F. Affixed in turn to planar shieldelectrode 10 and floating pad electrode F is a optional planar seconddielectric layer D2 shown at the bottom of the chuck structure. Seconddielectric layer D2 provides electrical isolation to shield electrode 10and floating pad electrode F by preventing access to air, where sparksor ionic discharges and breakdowns could occur. It also allows for usersafety, isolating the operator from high voltages.

Generally the outer, exposed face of second dielectric layer D2 as shownforms a bead contact surface BCS that is accessible to bombardment,contact or exposure to beads inside a grain dispenser or container, notshown.

FIG. 12 illustrate features of bead transporter chucks ("electrostaticchucks") at a collection zone that can be favorably employed in theinvention. The shield electrode 10 (also termed a "ground electrode"based on a preferred bias) is layered within a dielectric D, whichdielectric can be, for example, made of Kapton® (polyimide film, Dupontde Nemours, Wilmington, Del.)(Kapton® can be used as substrate materialfor Flexible Printed Circuits and can be etched in alkaline solutions,punched and laser drilled, and can be used to form multilayer polyimidefilm laminates). The grain-attracting electrode or bead electrode BEprojects out at the surface that attracts the planar substrate (whichis, for example, 1 mil thick) and can project out at the opposing sidewhere electrical contacts are formed. The width of the electrostaticchuck d can be, for example, 0.01 inches. As such, the electrostaticchuck can be relatively flexible. In the illustration, the planarsubstrate wraps over the outwardly projecting grain-attracting electrodeBE in a relatively close-fitting manner.

Generally, to attract and retain beads, the total electrical forceF_(elec) generated in the electric field E inside the grain dispenser orcontainer (not shown) on a grain with mass m and charge q must be equalto or greater, overall, than the force F_(grav) of gravity:

    F.sub.elec =Eq≧F.sub.grav =mg                       (5)

Upon applying a voltage to bead electrode 9, a grain attraction fieldE_(a) may be established, as shown pointing to the bead contact surfaceBCS. This attraction field E_(a) can cause beads to be attracted to andretained by an bead collection zone BCZ, as shown located on the beadcontact surface BCS to which the floating pad electrode F projects alongits planar axis.

Although the bead collection zone BCZ formed on the exposed portion ofsecond dielectric layer D2 is shown as being flat, it can also berecessed, beveled, bowl-shaped, or have any other profile that canfacilitate grain attraction, retention, and discharge, particularly ifattributes such as grain size selectivity are sought.

Electric fields, namely E_(a), in this and later figures are shown usingthe reverse of the standard convention, showing roughly the direction ofthe force on a negative test charge. This is because actual examples ofapplied voltages and grain charges in this disclosure use a workingconvention that negatively charged beads are to be attracted and, insome cases, later discharged. When manipulating positively chargedbeads, however, one can simply reverse the applied voltages from thosegiven in the discussion below.

As shown, bead electrode 9 is not exposed to the bead contact surfaceBCS or the bead collection zone BCZ. The electric field, however,generated by a potential applied to bead electrode 9 can emanate throughfirst dielectric layer D1 (and later through second dielectric layerD2), with the net electric field in the dielectric diminished byelectric polarization, depending on its dielectric constant ε, which canbe anisotropic. See Classical Electrodynamics 2nd Ed., John DavidJackson, ©1975, John Wiley & Sons, New York.

A voltage can be applied to bead electrode 9 relative to shieldelectrode 10 or relative to another surface in the grain dispenser orcontainer to allow attraction of beads to the bead collection zone BCZ.Bead electrode 9 can serve to provide an attraction field for one, orfor a plurality, of bead collection zones. Shield electrode 10 may haveany other potential applied to it, but it is typically held at groundpotential (zero volts) or repulsive potential with respect to the beadsto be manipulated.

To aid in visual confirmation of grain capture at the bead collectionzone BCZ, a hole (not shown) can be provided through any of beadelectrode 9, first dielectric layer D1, floating pad electrode F, andsecond dielectric layer D2. Such a hole provides a visual or opticalmonitor sight to verify if a grain is being retained. This allows forautomated verification of grain occupancy in the bead collection zone,using known sensors to determine the hole opacity in terms of percentlight transmission. For example, the light transmitted through such ahole can be optically mapped onto an array detector such as acharge-coupled device (CCD), an intensified CCD array, a focal planearray, or photodiode array. The array detector can be, for example, aCCD (such as that available from DALSA, Inc. (Easton Conn.), DavidSarnoff Research Center (Princeton N.J.) or Princeton Instruments(Trenton N.J.); an intensified CCD array (such as that available fromPrinceton Instruments, Hamamatsu Corp. (Bridgewater, N.J.) orPhotometrics Ltd. of Tucson, Ark.); a focal plane array (such as thatavailable from Scientific Imaging Technologies, Inc. (Beaverton, Oreg.),Eastman Kodak Co., Inc. (Rochester N.Y.) or David Sarnoff ResearchCenter); a photodiode array (such as that available from Reticon Corp.(Sunnyvale Calif.), Sensors Unlimited, Inc. (Princeton N.J.) orHamamatsu); or a photodetector array (such as that available from FLIRSystems Inc. (Portland Oreg.), Loral Corp. (New York N.Y.) or HughesElectronic Corp. (Los Angeles Calif.)).

When grounded or biased to a polarity similar to the grains to bemanipulated, shield electrode 10 can discourage grains from beingattracted or retained at any locations on the bead contact surface BCSother than the intended bead collection zone BCZ. However, shieldelectrode 10 can comprise any nonconductive material such as aninsulator or dielectric.

In lieu of dielectric layers D1 and D2, air or the ambient gas or vacuumcan be used as a dielectric or insulator. In this case, insulatedmechanical standoffs or other fasteners can be used to hold beadelectrode 9 in the same plane as, but offset from, shield electrode 10and floating pad electrode F. This can expose any of bead electrode 9,floating pad electrode F, and shield electrode 10 directly to the beadcontact surface.

Although the bead transporter chuck shown in FIG. 1 is given by way ofexample only, it should be said that fabrication techniques for formingits conductive layers and electrodes can vary considerably, as any knowntechnique satisfying modest electrical and mechanical requirements canbe used. Nearly any metal can be used, for example, to form electrodes9, F, and 10, which can individually comprise thermally orelectromagnetically deposited metals such as indium tin oxide, brass,platinum, copper, or gold, of any useful thickness, but preferably about1000 Angstroms to 10 microns (100,000 Angstroms). The same is true fordielectric layers D1 and D2--the materials used can be of any typecompatible with surrounding electrodes, and having sufficient dielectricstrength to withstand anticipated voltages applied, including ceramicmaterials; silicon dioxide; alumina; polyimide resins and sheets orother suitable polymers; metallic oxides, such as aluminum oxide andtitanium oxide; and titanates of calcium and magnesium. Dielectriclayers D1 and D2 can, for example, range in thickness from ten Angstromsto 1000 microns. The various layers can be assembled, if desired, usingwell known adhesives or deposition techniques.

Without being limited to theory, the discussion below sets forth anunderstanding of theory on how some of the bead transporter(electrostatic) chucks of the invention function. I should be understoodthat the bead transporter chucks function, and function under the ACelectrical driving protocols described herein, regardless of theaccuracy of the understandings set forth herein.

Now referring to FIG. 2, a partial cross-sectional view of the beadtransporter chuck of FIG. 1 is shown. Now, however, an attraction biasis applied to the bead electrode 9, and shield electrode 10 is grounded(zero volts). Resultant symbolic electrical charges are as shown. Usinga wire, conductor, cable, via, or bus (not shown), a positive potentialis applied to bead electrode 9 as shown, so as to attract and retainnegatively charged beads. This positive potential on bead electrode 9 isshown using a full row of positive symbols to indicate a positive netcharge there. This positive charge creates an electric field whichemanates through space, including downward on the page toward firstdielectric layer D1 (field lines omitted). As this positive electricfield traverses first dielectric layer D1, polarization in dielectriclayer D1 results in charge shifting, forming a certain induced electricdipole moment per unit volume. This induced electric dipole moment perunit volume is electrically equivalent to induced surface charge perunit area, appearing on both planar faces of first dielectric layer D1.This polarization cancels some, but not all, of the electric field dueto the potential applied to bead electrode 9, and this polarization isshown as a half-seeded row of negative and positive surface charges asshown at the planar faces of first dielectric layer D1. This forms aseries of electric dipoles--positive and negative charges separated by adistance--that, shown here for illustration, cancel half the electricfield inside first dielectric layer D1. For illustration purposes, thiscorresponds to a dielectric constant ε=2 (exactly) for first dielectriclayer D1.

The electric field experienced by the shield electrode 10, however, isin effect, governed by the laws of capacitors (see ref: Physics, 3rdEdition, by David Halliday and Robert Resnick, John Wiley & Sons, NY,©1978). Bead electrode 9 and shield electrode 10 as shown form acapacitor, with their mutual dielectric being dielectric layer D1.Accordingly, shield electrode 10 experiences a corresponding fullnegative charge, represented by the single full row of negative symbols.The result is that the projection of shield electrode 10 onto the beadcontact surface BCS is field-free, that is the electric field isessentially zero, ignoring minor fringe effects. In this sense, theshield electrode 10 acts as a Faraday shield, preventing any electricfield from emanating through it to the bead contact surface.

The situation is different, however, in the vicinity of the floating padelectrode F. Not connected to ground, and uncharged initially, thefloating pad electrode F can only rearrange its charges, and cannotsustain or have a net charge as do the bead electrode 9 and shieldelectrode 10 in this example. Furthermore, also being a conductor,charges in floating pad electrode F are free to move, not limited tosimple charge shifting exhibited during polarization. But like theshield electrode 10 above, the floating pad electrode F also forms acapacitor with bead electrode 9, with first dielectric layer D1 as theirmutual dielectric. As a result, charges in electrode F move internallyalong its planar axis, and the planar surface that floating padelectrode F shares with the first dielectric layer D1 displays a fullset of negative charges as shown. But since the net charge on floatingpad electrode F must be zero--it is electrically isolated--a full set ofpositive charges form on the planar surface of floating pad electrode Fthat it shares with the second dielectric layer D2.

Underneath, second dielectric layer D2 on its face shared with thefloating pad electrode F as shown, the net charge seen by the dielectricD2 is a full row of positive charges, just as the first dielectric layerD1 above saw a field consisting of a full row of positive charges. Thiscan be verified by canceling charges as shown. The result is againpolarization in second dielectric layer D2 in a manner similar to thatdescribed above for first dielectric layer D1.

In the vicinity of the bead collection zone BCZ, the electric fieldscreated thus far add up to an unbalanced or net charge (NET CHARGE), afull row of positive charges, as shown. This net charge is the chargethat is in theory available on the bead collection zone BCZ to attractnegatively charged beads and powders, and the electric attraction fieldit creates is represented by the attraction field E_(a) as shown. Onceenough negatively charged grain material lands and is retained on thebead collection zone BCZ, the available net or unbalanced charge goes tozero, and deposition usually ceases, unless beads in the vicinity areovercome by electrostatic image forces (see above).

Now referring to FIG. 3, a partial cross-sectional view as shown in FIG.2 is given, with a high-resistivity substrate (shown as SUBSTRATE) addedto the second dielectric layer D2 by contacting or being clamped to thebead transporter chuck so that it can receive grain deposition, such asduring preparation of drug administration forms. Resultant symbolicelectrical charges are again shown. For the components repeated here,the electrical behavior and arrangement of charges is as given above forFIG. 2, but now a relatively high resistivity (ρ=10¹⁵ Ω-cm, for example)substrate (SUBSTRATE) is added, firmly contacting the former beadcontact surface BCS on second dielectric layer D2 as shown on FIG. 2. Inthis case, the unbalanced net charge (NET CHARGE) which was availablefor grain attraction is now affected by the dielectric properties of thesubstrate. Thus, polarization again occurs (shown here symbolically forillustrative purposes are the effects of a dielectric material ofdielectric constant ε=2), with separated half-seeded charges shown asdone above for dielectric layers D1 and D2.

For a high resistivity substrate, the charge retention is good as afunction of time, being more or less constant, that is, the RC timeconstant is on the order of many minutes or hours, giving ample time forthe grain deposition process. Once again, the electric fields createdthus far, including now the substrate (SUBSTRATE), add up to anunbalanced or net charge (NET CHARGE), a full row of positive charges,as shown on the exposed portion of the substrate. This net or unbalancedcharge on the substrate surface creates a new bead collection zone BCZ.This net charge at the bead collection zone BCZ is available to attractnegatively charged grains such as powders. The electric field it createsis again represented by the attraction field E_(a) as shown. Once enoughnegatively charged grain material lands and is retained on the new beadcollection zone BCZ on the substrate surface, the available net orunbalanced charge--and the resultant electric field or voltage on thebead collection zone BCZ--go to zero, and deposition is no longerexplicitly encouraged.

Now referring to FIG. 4, another partial cross-sectional view is givenreproducing the elements shown in FIG. 3, but now SUBSTRATE is alow-resistivity substrate (e.g., ρ=10¹¹ Ω-cm) contacting or clamped tothe bead transporter chuck, and some time greater than a few timeconstants has passed.

The lower resistivity substrate (SUBSTRATE) no longer acts as adielectric. The resistivity is low enough that the RC time constant asmentioned above is on the order of milliseconds. After a few timeconstants have passed--generally not enough time for grain attraction ordeposition--the substrate undergoes internal flow or movement of chargesthat leak out or cancel the unbalanced or net charge (NET CHARGE) shownin FIG. 3. In this substrate as shown, negatively charged carriers havenot simply shifted, but have moved, macroscopically through thesubstrate. These negative charges in the substrate cancel the net chargethat would have accrued on the surface, as shown in FIG. 3. Humidity andairborne dust can play a role in this process, helping to dissipateinduced charge on the substrate. This stray environmental dissipation ofcharge allows that the substrate does not necessarily have to become orremain positively charged overall for very long for this to happen. Withno remaining net or unbalanced charge left over at the bead collectionzone BCZ on the substrate surface, no potential or voltage exists tomove or accelerate grains. The grain attraction field E_(a) becomeszero, as shown.

This can be seen visually, using the symbolic charges, by countingcharges and cancelling. Certain compensating positive charges that mayreside at edges of the substrate are not shown for clarity.

Referring to FIG. 6, an equivalent circuit is shown that canschematically represent the electrical behavior of the bead transporterchuck of FIGS. 3 and 4. It shows main influences in terms ofcapacitances and resistances and serves as an illustration only. Theapplied voltage or bias on bead electrode 9 is shown as Bias (V₉),originating from a power source, not shown. Bias V9 is applied across acapacitance CF comprising first dielectric layer D1 to floating padelectrode F, shown as Pad F. Pad F is in turn affected by straycapacitance C_(F-stray), forming a equivalent capacitor with the shieldelectrode 10 and possibly the ambient air or fluid inside the chuck,depending on its construction.

Floating pad electrode F in turn is coupled to another chargetransferring element--the bead collection zone BCZ at the exposedsurface of the substrate (shown as BCZ on top of exposed substrate).Significant elements here include resistance. Floating pad electrode Facts as a capacitor with the bead collection zone BCZ, with the seconddielectric layer D2 as the dielectric, with an equivalent capacitanceshown as C_(S). This coupling between floating pad electrode F and thebead collection zone BCZ also has a resistance R_(S) associated with it,mostly from resistivity of the substrate itself, that is, for charges tomigrate to the exposed substrate surface.

Finally, the bead collection zone BCZ on the exposed substrate iscapacitively coupled to ground--via the shield electrode 10, thesubstrate, and through humidity and other local environmental factors.The equivalent capacitance is shown as C_(S-stray). C_(S-stray) derivesits value from the capacitance of second dielectric layer D2, thesubstrate, and from local environmental factors, like dust and humidity.The coupling between the bead collection zone BCZ and ground also has aresistance R_(S-stray) associated with it as shown, mostly fromresistivity of the substrate itself and that of second dielectric layerD2.

Now referring to FIG. 7, three Cartesian graphical waveforms are shownto represent applied and resultant voltages in the bead transporterchuck as a function of time, where a low-resistivity substrate isapplied thereto (as in FIG. 4), and using traditional quasi-staticbiasing. The voltage versus time waveform labeled V₉ represents thevoltage applied to the bead electrode 9. As shown, after approximately40 mS, the voltage is switched on, and remains at some desired level inan attempt to induce grain attraction and retention.

The voltage versus time waveform labeled V_(BCZ) represents the voltageor electric potential, grain attraction potential, that exists on thebead collection zone BCZ on the exposed portion of the substrate. Inthis case, it is the amount of charge that is retained--that is,undistributed, not leaked away--on the surface of the substrate at thebead collection zone BCZ, such as that shown at the bottom of FIG.3--that determines the voltage V_(bcz). This unbalanced charge is whathelps determine the resultant potential voltage on the floating padelectrode F, shown in the waveform labeled V_(Pad) F.

No grain or powder deposition is shown or demonstrated in these voltagecurves. Upon application of the bias potential to bead electrode 9,shown by the steady high state value in V₉, both V_(Pad) F and V_(BCZ)shoot up to high state values, representing a full unbalanced chargepresent at the bead collection zone BCZ and therefore the floating padelectrode F. Then, both potentials V_(Pad) F and V_(BCZ) undergo acharacteristic RC time constant decay. This is due directly to thecurrents or motion of charge carriers in the substrate responding to theapplied field at bead electrode 9. The charge rearrangement in the lowresistivity substrate leaks off the unbalanced charge on the beadcollection zone BCZ on the substrate surface. After one characteristictime constant, both potentials V_(Pad) F and V_(BCZ) fall to about(1/e), or approximately 37% of their final steady state values. Thismeans that only 37% of the initial charge present on the bead collectionzone BCZ of the substrate surface remains. Often, within milliseconds,the charge Q remaining goes to virtually zero, and the bead transporterchuck stops working.

Referring now to FIG. 8, three Cartesian graphical waveforms are shownrepresenting the same applied and resultant potentials in the beadtransporter chuck as given in FIG. 7, but where the problem ofattracting beads to low resistivity substrates is solved, using ACwaveforms biasing at the bead electrode 9. As shown, bead electrode 9bias V₉ comprises a single polarity pulse of limited duration, about 40mS. The pulse, labeled Pulse is approximately a square wave, and canhave, for example, a peak value of 2000 volts positive, for attractionof negative beads. During the high state value of the pulse, the profileof V_(Pad) F and V_(BCZ) are as before in FIG. 7--charge on the beadcollection zone BCZ and floating pad electrode F is built up quickly toa maximum value, then immediately starts leaking away, as discussedabove.

However, just as much of the charge on the bead collection zone BCZ hasleaked away, the Pulse bias V₉ is brought back to zero, as shown.V_(Pad) F and V_(BCZ) then relax, decreasing rapidly and then perhapsovershooting somewhat, and switching polarity because ofopposite-polarity leakage charges that remain close to the beadcollection zone BCZ and have not yet moved back to their formerpositions. After an interval--and this temporal spacing is determined bythe relevant time constants involved--the offending leakage chargecarriers have dissipated, and the bias pulse V₉ is then administeredagain, as shown. These periodic waveforms provide momentary impulsesthat allow grain attraction to take place even though the charge leakagein and across the substrate is substantial. These single polarityperiodic pulses may be generated by known power supplies, includingthose using step-up transformers so that AC bias waveforms with voltagesin the kV range may be generated by simple inexpensive power supplies atmuch lower voltages. This is possible because the actual high voltagecurrent flow into the chuck can be as low as the nano-Ampere range.

With the aid of the electrostatic image force on charged beads, thistechnique has been found to work for low resistivity substrates ofρ=10¹⁰ Ω-cm, and perhaps lower. The frequency of single polarityperiodic pulses must be low enough, however, for the beads to respond.Essentially, the attractive field E_(a) provided by providing AC biasingat the bead electrode 9 must act long enough temporally to have thebeads experience an attractive force for some time and have a chance toaccelerate by overcoming inertia and collisions with other beads. If thefrequency of the periodic waveform at V₉ is too high, the appliedvoltage operatively takes on attributes of quasi-static biasing, and thetime-averaged leakage current becomes more effective in draining the netcharge on the bead collection zone.

There is a broad range of possible bias waveforms and of workablefrequencies, and empirically-based adjustments can provide a good sourceof values for optimal frequencies. For example, a single polarityperiodic set of square wave pulses, of frequency of about 4 Hertz, andpeak voltage value durations of about 40 mS works well. It has also beendiscovered that grain powder charged to 10 mC/g will respond to periodicpulses of up to 100 Hertz frequency. This technique also allowssatisfactory operation of bead transporter chucks at high relativehumidity, such as 50-60% humidity. Active ingredient dosage depositsranging from 300-800 micrograms are obtained (e.g., on 4 mm diametercollection zones), on low resistivity substrates where higher amountdepositions were previously difficult.

Even on higher resistivity substrates having an RC time constant on theorder of minutes or hours, AC waveform biasing can help to mitigate theaction of residual surface charges that migrate and help dissipate thenet charge used to attract beads at the bead contact surface.

Referring now to FIG. 9, the necessary attributes of an effective ACbias periodic potential or waveform can be illustrated, using theexample of a single polarity square waveform from FIG. 8. FIG. 9 givesanother cartesian graphical waveform representing the potential at thebead collection zone BCZ as a function of time, shown magnified withrespect to the previous figure. It shows the grain attraction potentialV_(BCZ) on the substrate that results from the pulse waveform shown inFIG. 8, except that the square wave pulses delivered to the beadelectrode 9 (shown as V₉) occur more frequently, with less temporalspacing.

Starting at point A as shown, the potential V_(BCZ) on the substratesurface rises rapidly in response to the single polarity square wavepulse (V₉) delivered to bead electrode 9. As before, leakage processescause unwanted charge cancellation at the substrate surface, and acharacteristic RC decay of the potential V_(BCZ) occurs. This is shownlabeled Decay. During the next phase, the applied square wave potentialV₉ drops to zero, and a recovery phase, labeled Recovery, begins. Duringrecovery, the potential V₉ is zero or can simply have some lower valuethan its peak value. In this example, V₉ goes to zero, and in theinitial part of the recovery phase, V_(BCZ) in turn goes to zero. Thenbecause of charge leakage in the reverse direction that has not yetcompletely occurred to bring about a return to equilibrium, V_(BCZ) canmomentarily overshoot and go negative, as shown between points labeled Band C.

So long as V_(BCZ) is positive, such as shown between points A and B,grain attraction can take place. This part of the potential wave forV_(BCZ) is labeled attractive. When V_(BCZ) reverses polaritymomentarily during the recovery phase, as shown between points B and C,the bead collection zone BCZ on the substrate or bead contact surfacebecomes repulsive (typically mildly repulsive) to properly chargedbeads; this is shown labeled repulsive.

The pulses of the AC bias waveform for V₉ can be put close together, soas to place the potential waves for V_(BCZ) close together as shown,minimizing the time when V_(BCZ) is zero or close to zero. This improvesthe time-averaged characteristics of the potential at the beadcollection zone BCZ.

The possible AC biased waveforms V₉ that may be applied to the beadelectrode 9 can vary widely in character. The AC bias applied maycomprise a mixture of AC and DC components and may be mixed, comprisingsquare wave, sinusoidal, saw tooth, and other waveforms and theirmixtures. For example, the waveform given here can be added to a fixedDC potential of, say 200 volts, elevating the pulsed waveforms.

The AC bias voltage pattern chosen for V₉ should preferably be chosen tomaximize the time averaged or cumulative potential at the beadcollection zone BCZ during a single periodic repetition of the waveform,or, if the waveform is aperiodic, during the time needed for grainattraction. This may be achieved for this example by choosing a V₉waveform that maximizes the integral of the absolute value of V_(BCZ)with respect to time, between points A and B, that is, maximize ##EQU2##where A and B are time values at points A and B on FIG. 9. In a similarmanner, if a given AC bias V₉ waveform produces significant repulsivebehavior during the recovery phase, one can choose or alter a V₉waveform that minimizes the integral of V_(BCZ) with respect to time,between points B and C, that is, minimize ##EQU3## where B and C aretime values at points B and C on FIG. 9. For particularly effectivetime-averaged values of V_(BCZ) that provide maximum motive force forbeads that need to overcome collisions and other obstacles, one caninstead choose AC bias V₉ waveforms that maximize V_(BCZ) raised to somepositive power greater than one, such as maximizing its square over thetime interval from point A to point B, that is, by maximizing ##EQU4##which would encourage temporal emphasis on high values of V_(BCZ) byweighting the average in favor of values of V_(BCZ) that are close topeak or maximum.

This optimizing of the V₉ waveform functionality for a given chuck canbe calculated beforehand, even without much empirical study, byempirically measuring values for the resistances and capacitances, thatis, C_(F), C_(F-stray), C_(S), R_(S), C_(S-stray), and R_(S-stray), ofthe equivalent circuit discussed in FIG. 6. By using known equations forthe circuit as shown, or any other equivalent circuit that applies tothe bead transporter chuck in question, one can use computeroptimization or other numerical techniques to calculate what form thepotential V_(BCZ) takes upon stimulation by any proposed V₉ waveform.

In any case, the AC waveform bias or potential V₉ will be chosen so thatthe time average of the grain attraction potential V_(BCZ) that resultson the bead collection zone is greater, on average, than that that wouldbe obtained when applying an equivalent time-averaged DC potentialV_(9-DC) --perfectly rectified and smoothed--that corresponds to the ACwaveform potential V₉ at the bead electrode 9. With V_(BCZ) obtainedusing the AC waveform potential V₉, we can use the name V_(BCZ-DC) forthe grain attraction potential that results from using the time-averagedDC potential V_(9-DC). That is:

V_(BCZ) results from use of AC bias potential V₉,

V_(BCZ-DC) results from use of DC equivalent bias V_(9-DC).

The time-averaged DC potential V_(9-DC) can be calculated bytime-averaging the AC waveform bias V₉ by taking the integral of V₉divided by time t, with respect to time: ##EQU5##

For example, if a square wave is used for V₉ that consists of 1000 voltpeaks that occur 50% of the time, but is zero at other times, theequivalent time-averaged DC potential V_(9-DC) will be equal to 500volts. The grain attraction potential V_(BCZ), on average, that resultsfrom using the 1000 volt AC waveform peaks will be greater than thatobtained by applying a plain 500 volts DC to bead electrode 9.

This means that the integral of the absolute value of V_(BCZ) over theattraction phase from point A to point B, divided by time t, is greaterthan the integral of V_(BCZ-DC) obtained when using the equivalenttime-averaged DC potential, V_(9-DC) at the bead electrode 9, or##EQU6## Time t shall be chosen to have only positive values.

Even if the V₉ waveform chosen for application to the bead electrode 9results in significant repulsive behavior, grain attraction will stillbe well served, because the attraction periods in the V_(BCZ) waveformwill be more effective than the repulsion periods. This is mostlybecause of the electrostatic image force that beads will experience uponnearing the chuck, regardless of the actual V_(BCZ).

In the vicinity of the bead transporter chuck, with a charged grain at adistance d from any conductive surface in the chuck, the electrostaticimage force, F_(image), due to the image charge can become, as the grainnears the chuck, more significant than the force F_(elec) given above.Roughly, the dependence of the electrostatic image force on the distanced for a given charge q on a grain, is as follows, using Coulomb's Lawfor stationary point charges: ##EQU7## In the denominator, ε₀ is thevacuum permittivity; (πd³ /6) is the grain volume; ρ is the grain massdensity in kg/m³ ; and g is the acceleration due to gravity. This givesthe electrostatic image force in units of g. This can become a potentforce at short distances, but the grain attraction field E_(a) is stillneeded to bring charged beads within its influence.

Other techniques may be used simultaneously to enhance bead transporterchuck effectiveness, including use of periodic air or fluid flowprovided acoustically by a conventional speaker. Such a speaker (notshown) can be in fluid communication with some part of the graindispenser or grain manipulation theatre, so that it may direct acousticenergy to unseat beads that are held by electrostatic image forces todispenser surfaces, or during grain discharge at a desired target, tounseat grains held by electrostatic image forces to the chuck itself.

The use of AC bias waveforms for the bead electrode 9 also solvesanother longstanding problem during deposition sensing. Duringdeposition sensing, one or more bead collection zones are closelymonitored for grain accumulation, so as to allow regulation of the graindeposition process, to produce for example precise dosages. This can bedone optically or by measuring accumulated charge using an "on-board"charge sensor at a sensor-associated bead collection zone, which can becorrelated to actual charged grain deposition by empirical datacollection. In dry powder deposition, for example, dose monitoring isoften a very difficult task, particular for dosages below one milligram.

The difficulty is not that measuring devices are not available--modemsolid state devices, although expensive, can make measurements soprecise that noise levels are on the order of the voltage generated bythe charge of a few hundred electrons. Rather, the difficulty lies withvarious practical and environmental factors that can deteriorate chargesensing sensitivity by two or three orders of magnitude. Forquasi-static DC biased bead transporter chucks, on-board charge sensingis particularly difficult. Data obtained by depositing on apolypropylene film substrate with different potentials indicates thatthe deposited dose is linearly related to the bias potential if thatpotential is above a certain threshold potential. Data indicates thatthreshold potential is about 100-200 volts DC, at least for certaintransporter chucks.

Referring now to FIG. 10, one possible equivalent circuit diagram thatprovides AC biased charge and deposition sensing for at least one of thebead collection zones of the bead transporter chuck shown in FIGS. 1-4is shown. One or more bead collection zones BCZ are typically dedicatedsolely for sensing or are in general use, but closely monitored. Bymeasuring the lowering of the attraction potential V_(BCZ) that occursas charged beads deposit on the bead collection zone, a measure ofdeposited charge can be obtained, and by knowing the average charge/massratio q/m of the deposited grains (e.g., beads or powder), theaccumulated grain deposition mass can be measured. One can measureV_(BCZ) directly across a charge collector electrode, but it is oftenpreferable to measure the potential across a coupling capacitor, such asthe floating pad electrode F discussed above, whose waveform is shown inFIG. 8. The coupling capacitor as embodied by floating pad electrode Fabove will provide reasonably high fidelity reproduction of thepotential at the bead collection zone BCZ on the bead contact surface,and in FIG. 8 the waveforms for V_(BCZ) and V_(Pad) F reflect this. Ineither case, whether a charge collector or charge coupling capacitor isused, they may both be considered charge sensing electrodes, such as inthe appended claims. In the equivalent circuit of FIG. 10, the chargecollector/coupling capacitor is electrically connected to a separatesensing capacitor. The voltage generated across the sensing capacitorcan be a reliable indicator of the potential V_(BCZ), and one simplymeasures the voltage across the sensing capacitor with an electrometer,such as a Keithley model no. 614, 6512, 617, 642, 6512, or 6517Aelectrometer, as shown schematically in the figure. Generally thecoupling capacitor is any electrode that is capacitively coupled to abead collection zone on the bead contact surface.

A problem is that DC biasing can cause a steady drift in the reading ofthe potential across the sensing capacitor. This drift comes from manysources, mostly from natural leakage across the dielectric material inthe sensing capacitor, and because of charge leakage in the substrate orgrain composition on the accumulated on the chuck. Drift can also beinduced by noise factors such as shot noise, Johnson (1/f) white noise,thermal noise, Galvanic noise, triboelectric noise, piezoelectric noise,amplifier noise, and electromagnetically induced noise. See ref: The Artof Electronics, by Paul Horowitz, Winfield Hill, 2nd Edition, CambridgeUniversity Press, ©1989 ISBN 0521370957, which is incorporated as areference in its entirety.

If this drift is too large compared to the actual charge collected atthe bead collection zone, the accuracy of the charge sensor as a dose ordeposition measurement tool can be unacceptably low. Using AC biasedwaveforms as taught here, however, minimizes the creation of drift, in amanner similar to that used above for avoiding the "drift" of chargedissipation on the bead collection zone, allowing precise measurement ofcharge collected. As shown on the figure, an AC bias source is shown,and may simply be the same source as discussed above, with the AC biaspotential simply applied or administered via the bead electrode 9. Thiswill in turn electrically couple to the floating pad electrode F or tothe bead collection zone itself, if one elects to connect it directly tothe sensing capacitor as shown.

For example, if the sensing capacitor is chosen to be 0.1 μF, and theq/m of the powder is 10 μC/g, a 100 mV signal change on the chargecollector/coupling capacitor corresponds to 1 mg of powder deposited onthe bead collection zone. If, say, the linear correlation factor is 3,then 1 mg of powder on the sensor corresponds to 3 mg of powder in theactual deposition dose, then a 99 μg actual dose will have a detectablepotential change of 3.3 mV. With a 5% error tolerance, the correspondingbackground unpredictable noise contribution cannot exceed 160 μV. Thisis achievable with careful shielding and grounding design. Preferablythe charge collector is integrated with the chuck design to assure aconsistent correlation.

In effect, the same benefits gained by using the AC bias waveforms forV₉ to avoid charge dissipation in the substrate can be used to greatlyreduce drift in the charge sensing circuit, too.

Referring now to FIG. 11, another possible equivalent circuit diagramthat provides AC biased charge and deposition sensing is shown. Thisarrangement further reduces noise by separating the AC bias source fromthe electrometer, the sensing capacitor or the charge collector/couplingcapacitor, all components whose sensitivity to noise is critical. Asshown in the figure, the AC bias source is connected to the primary ofan transformer T. In this manner, only the periodic magnetic fieldgenerated by V₉, (not V₉ itself) is introduced into the sensitivecomponents on the right side of the figure. The secondary winding oftransformer T is connected across a stabilizing bleed resistor R, withone pole, biasing pole BP connected to the charge collector/couplingcapacitor, and the other pole, the sensing capacitor pole CP connectedto the sensing capacitor. To further reduce noise, the sensing capacitoris connected to ground. The electrometer can then measure the voltagechange on the sensing capacitor with respect to ground, as shown. Thesetwo grounding points can be combined to reduce electromagnetic noisefurther. The transformer T can be a step-up transformer as discussedabove so that complex AC bias waveforms supplied here and to the beadelectrode 9 can be generated inexpensively. For example, the step-upratio can be 50. This arrangement greatly reduces drift and makeaccumulated charge sensing more accurate, where previously the couplingcurrent of 100 pico-Amperes or less made drift and noise a real problem.

If desired, transformer T can be an isolation transformer, where theprimary and secondary windings are separated by a Faraday cage. This canprevent coupling between the primary and secondary windings, where theprimary winding acts as one capacitor plate, and the secondary as theother capacitor plate.

With this improved signal to drift ratio, the amount of charge sensedcan decrease substantially. Measurements can now be made using a 1000picoF capacitor as the sensing capacitor instead of the 0.1 μF valueused previously. Also, the AC bias source as shown in FIGS. 10 and 11can be separate from the AC waveform bias V₉ on the chuck, by deliveringa separate AC bias to the charge collector/coupling capacitor directly,via a dedicated wire, electrode, bus, etc. This separate AC bias can befrequency matched or detuned with respect to V₉ to insure consistentcorrelation of the behavior of the charge collector/coupling capacitorto actual depositions.

Overall, too, these techniques allow V₉ biasing with voltage peaks muchhigher than previously possible. Using 8000 molecular weightpolyethylene glycol as a substrate, bias peaks of 2 kV have been used.It is important also to keep in mind that any kind of bead transporterchuck can be used, including those that operate with bias electrodesdirectly exposed to the bead contact surface (such as illustrated inFIG. 12).

In practice, one introduces charged grains into the grain dispenser orcontainer (not shown). For attracting and retaining negatively chargedgrains, for example, one can apply a negative bias to a conductivesurface in the grain container and/or a tribo-charging mesh, and apositive bias to the bead electrode 9, while a grounded shield electrode10 or a negatively biased shield electrode 10 helps guide grains totheir intended destinations at the bead collection zones BCZ. This willfunction in sorting out grains according to polarity and charge/massratio, with grains of a certain charge/mass ratio and correct polaritybeing encouraged to seat themselves at the bead collection zones.

Available grain compositions are well known in the art, and aretypically polymer-based, such as divinylbenzene copolymer; polystyrene;polyethylene glycol; or polyethylene glycol graft polystyrene, such assupplied under the trade name PEG-PS by PerSeptive Biosystems ofFramingham, MA; or cross-linked polyethylene glycol resin, as suppliedby Rapp Polymer GmbH of Germany. Grains can be dry, or may have absorbedor adsorbed an aqueous solution, or a fine powder, such as a micronizedpowder. Grains can also be, for example, dry paint or phosphorparticles, or any other powders that can be charged, such astriboelectrically or by induction charging. The invention is very suitedto depositing pharmaceuticals in a controlled manner onto substrate thatcan be used to form drug delivery vehicles. Dry deposition techniques asoutlined herein allow excipients to be minimized in such formulations,which can facilitate quality control and eliminate issues of materialsinteracting in a deleterious fashion.

Grains can be charged prior to their application to the bead transporterchuck, for example, using plasma charging, or by the use oftribocharging (rubbing or contact charging) as known in the art.Materials that can be used for tribocharging includepolytetrafluoroethylene (TEFLON®), and polymers ofchlorotrifluorethylene, chlorinated propylene, vinyl chloride,chlorinated ether, 4-chlorostyrene, 4-chloro-4-methoxy-styrene, sulfone,epichlorhydrin, styrene, ethylene, carbonate, ethylene vinyl acetate,methyl methacrylate, vinyl acetate, vinyl butyral, 2-vinyl pyridinestyrene, nylon and ethylene oxide. See, for example,"Triboelectrification of Polymers" in K. C. Frisch and A. Patsis,Electrical Properties of Polymers (Technomic Publications, Westport,Conn.), which is hereby incorporated by reference in its entirety. Alsosee Handbook of Electrostatic Processes, Jen-shih Chang, Arnold J.Kelly, and Joseph M. Crowley, eds., Marcel Dekker, Inc., New York,©1995. For example, polytetrafluoroethylene and polyethylene and othermaterials that become negatively charged tend to create a positivecharge on the grain or object. Nylon and other materials that becomepositively charged will tend to create a negative charge on the grain orobject. When using mechanical shaking to tribocharge polymer beads, itis preferred that the ratio of the amount or mass of tribochargingmaterial used to charge the beads to the amount or mass of beads is suchthat their respective total surface areas are about equal.

In the course of using the bead transporter chucks, a number ofoperating modes can be used. For grain pickup or retention, a beadelectrode, either exposed or unexposed to the bead contact surface, iselectrically biased to attract grains, while other conductive surfacesin the grain dispenser or container can be biased oppositely. Any numberof bead electrodes 9 can be used, and they can be individually andseparately connected by known means to facilitate individual andselective addressing in two dimensions.

Once attracted and retained, grains on the bead transporter chuck areoptionally transported to a substrate, microtiter plate, or otherdestination by moving the entire bead transporter chuck, oralternatively, the target substrate or plate is brought to the chuck.Beads are then released or discharged in a controlled manner when any orall of the applied voltages are reversed or set to zero. For example,for grain release, only the bead electrode 9 can be shorted out orgrounded (0 volts), or have an opposite voltage applied. Optionally,when shield electrode 10 is used, it can be biased to be repulsive tograins during grain discharge. Acoustic releasing mechanisms orprocesses can be used to aid in grain discharge and placement.

When using bead transporter chucks according to the present invention,the temperature is preferably between -50° C. and 200° C., and morepreferably between about 22° C. and 60° C. Relative humidity can be0-100 percent, so long as condensation does not occur; more preferablythe relative humidity is about 30 percent.

Bead electrodes 9 can comprise any number of separately addressablepixels or elements in two directions x and y, each having separatelycontrolled bead collection zones. Any number of well known means andstructures can be used to facilitate addressing as is known in theelectrical and electronic arts. In this way, combinational synthesis oranalysis can be simplified as discussed above. In using the beadtransporter chucks, one can expose the bead contact surface of such achuck to grains; selectively apply AC waveform voltages, such as thevoltages given above, for each x-y addressable well, pixel, orindividual spatial element of the chuck, to attract and retain grainsselectively at each bead collection zone; then release the grains onto adesired destination aligned with the bead transporter chuck byselectively reversing or reducing voltages associated with each beadcollection zone as required.

It is also possible that grains attracted by the chuck, especially largediameter grains or objects of large overall size, say 3 mm in diameter,and having low resistivity, can become viable substrates, to be coatedwith a pharmaceutically active compound. Such grains could includeoblong shapes, made of water soluble film, such as hydroxypropyl methylcellulose resin. See U.S. patent application Ser. No. 08/471,889,"Methods and Apparatus for Electronically Depositing a Medicament PowderUpon Predefined Regions of a Substrate," filed Jun. 6, 1995, now U.S.Pat. No. 5,714,007, and continuation-in-part thereof filed Jun. 6, 1996,Ser. No. 08/659,501, which documents are incorporated herein byreference in their entirety.

In this way, electrostatic chucks using low resistivity substrates,e.g., low resistivity substrates, can be scaled up for large scalecontinuous manufacturing, such as using a sheet of an edible substratefor use with tablets, for example, or a sheet of an inhaler substrate.For example, hydroxypropyl methyl cellulose can be used, such as EdisolM Film M-900 or EM 1100 available from Polymer Films Inc. (RockvilleConn.). Generally, sizing of grain diameters can range from less thanone micron to 1000 microns or larger.

Obviously, many modifications and variations of the present inventionare possible in light of the above teaching. It is therefore to beunderstood, that within the scope of the appended claims, the inventioncan be practiced otherwise than as specifically described or suggestedhere.

All publications and references, including but not limited to patentsand patent applications, cited in this specification are hereinincorporated by reference in their entirety as if each individualpublication or reference were specifically and individually indicated tobe incorporated by reference herein as being fully set forth. Any patentapplication to which this application claims priority is alsoincorporated by reference herein in its entirety in the manner describedabove for publications and references.

While this invention has been described with an emphasis upon preferredembodiments, it will be obvious to those of ordinary skill in the artthat variations in the preferred devices and methods may be used andthat it is intended that the invention may be practiced otherwise thanas specifically described herein. Accordingly, this invention includesall modifications encompassed within the spirit and scope of theinvention as defined by the claims that follow.

What is claimed:
 1. An electrostatic chuck for attracting charged grainsto a bead collection zone on a bead contact surface comprising:a beadelectrode for selectively establishing a grain attracting field to thebead collection zone, the bead electrode shaped and configured in such amanner so that when an AC waveform potential is applied thereto, thegrains are influenced by it and guided to selective retention by thebead electrode to the bead collection zone; and an electronic driverprogrammed to deliver the AC waveform potential configured to provide arepeated effective grain attraction potential at the bead collectionzone, wherein the AC waveform potential comprises a grain-attractingpotential pulse followed by a recovery period adapted to allow, in thecase where the bead collection zone is formed on a substrate with aresistivity below 10¹¹ Ω-cm, an effective grain attraction field at thebead collection zone on activation of a subsequent grain-attractingpotential pulse, wherein the AC waveform potential has a frequency of100 Hz or less.
 2. The electrostatic chuck of claim 1, furthercomprising a shield electrode which is shaped and configured to allow anelectric field from the bead electrode to emanate through the beadcollection zone.
 3. The electrostatic chuck of claim 1, furthercomprising a floating pad electrode capacitively coupled to the beadelectrode, wherein charge redistributions in the floating pad electrodein response to a potential applied to the bead electrode establish thegrain attracting field.
 4. The electrostatic chuck of claim 3, furthercomprising a shield electrode positioned and configured as to surround,but remain electrically isolated from, the floating pad electrode. 5.The electrostatic chuck of claim 1, further comprising a chargecollector electrode for monitoring accumulated charge on the beadcollection zone of the bead contact surface.
 6. The electrostatic chuckof claim 1, further comprising a coupling capacitor positioned betweenthe bead electrode and the bead contact surface, the coupling capacitorcapacitively coupled to the bead collection zone on the bead contactsurface.
 7. The electrostatic chuck of claim 1, wherein the electronicdriver is programmed to deliver the AC waveform potential configuredsuch that the grain attraction potential on the bead collection zone isgreater, on average, than that obtained when applying a time-averaged DCpotential corresponding to the AC waveform potential.
 8. Theelectrostatic chuck of claim 7, where the electronic driver isprogrammed to provide the AC waveform potential to maximize a grainattraction potential at the bead collection zone of the bead contactsurface.
 9. The electrostatic chuck of claim 1, wherein the electronicdriver is programmed to deliver the AC waveform potential configured toprovide a repeated effective grain attraction potential at the beadcollection zone when the bead collection zone is formed on a substratewith a resistivity below 10¹⁰ Ω-cm.
 10. An electrostatic chuck devicewith an accumulated charge sensing circuit having a charge sensingelectrode for monitoring accumulated charge on the bead collection zoneof the bead contact surface, comprising:an AC bias source; anelectrostatic chuck comprising at least one a bead electrode forestablishing a grain attracting field to attract charged grain s to abead collection zone the electrostatic chuck further comprising asensing capacitor electrically connected between a charge collectorelectrode and the AC bias source; and an electrometer electricallyconnected between the AC bias source and a coupling capacitor to measurethe potential of the sensing capacitor.
 11. An accumulated chargesensing circuit of claim 10, comprisinga transformer having a primarywinding and a secondary winding, wherein the primary and secondarywindings each have first and second poles; the charge collectorelectrode electrically connected to the first pole of the secondarywinding of the transformer; the sensing capacitor connected between aground and the second pole of the secondary winding of the transformer;the electrometer electrically connected between the second pole of thesecondary winding of the transformer and a ground; and the AC biassource connected across the first and second poles of the primarywinding of the transformer.
 12. A method for adhering charged trains toa bead collection zone on a bead contact surface comprising:(1) adheringa substrate with a resistivity below 10¹¹ Ω-cm to an electrostaticchuck, with the substrate arrayed over a grain-attracting electrode ofthe electrostatic chuck so that a surface of the substrate defines thebead contact surface; (2) applying an AC waveform potential to thegrain-attracting electrode to create a grain attracting field, whereinthe AC waveform potential comprises a grain-attracting potential pulsefollowed by a recovery period adapted to allow an effective grainattraction potential at the bead collection zone on activation of asubsequent grain-attracting potential pulse, wherein the AC waveformpotential has a frequency of 100 Hz or less; and (3) attracting andretaining a grain to the bead collection zone.
 13. The method of claim12, additionally comprising:(4) reducing a first potential applied tothe bead electrode, thereby reducing the grain attracting fieldsufficiently to discharge a grain from the bead collection zone to adesired location.
 14. The method cf claim 12, additionallycomprising:(5) providing an accumulated charge sensing circuit for thebead transporter chuck having a charge sensing electrode for monitoringaccumulated charge on a bead collection zone of the bead contactsurface, comprising(a) an AC bias source, (2) a sensing capacitorelectrically connected between the charge collector electrode and the ACbias source, and (b) an electrometer electrically connected between theAC bias source and the coupling capacitor to measure the potential thesensing capacitor; (6) terminating the application of the AC waveformpotential when the charge sensing circuit indicates that sufficientgrains have been accumulated at the bead collection zone, or, wherethere are multiple bead collection zones and two or more charge sensingcircuits, adjusting AC waveform potentials so that grain accumulation atvarious bead collection zones is adjusted.
 15. The method of claim 12,wherein the AC waveform potential is effective to apply at least 300μg/4 mm of charged powder to a said bead collection zone.
 16. The methodof claim 12, wherein the AC waveform potential is configured to providea repeated effective grain attraction potential at the bead collectionzone, even where a substrate defining the bead contact surface has aresistivity below 10¹⁰ Ω-cm.
 17. The method of claim 16, wherein the ACwaveform potential is effective to apply at least 300 μg/4 mm of chargedpowder to a said bead collection zone.
 18. The method of claim 12,wherein the AC waveform potential is configured such that the grainattraction potential at the bead collection zone is greater, on average,than that obtained with a time-averaged DC potential corresponding tothe AC waveform potential.
 19. The method of claim 12, wherein the ACwaveform potential is chosen to maximize a grain attraction potential atthe bead collection zone of the bead contact surface.
 20. The method ofclaim 12, wherein the grains are a micronized powder.
 21. The method ofclaim 12, comprising fabricating dosage forms by:providing an ediblesubstrate as the substrate; and operating the electrostatic chuckpursuant to steps (1) through (3) to deposit measured amounts of powder,comprising a pharmaceutically active substance, on spatially resolvedregions of the edible substrate.
 22. The method of claim 12, wherein theAC waveform potential has a frequency of 25 Hz or less.